Sleep Disorders
Milena Pavlova
EXCESS DAYTIME SLEEPINESS
Background
Nearly a quarter of healthy adults have excessive daytime sleepiness. There are many causes including insufficient or ill-timed sleep (ie, jet lag or voluntary sleep restriction), primary sleep disorders, as well as medical and neurologic disorders that disrupt sleep or produce pathologic sleep states.
History
1. The typical complaint is of falling asleep unintentionally, causing embarrassment, loss of productivity, and sometimes being hazardous (eg, while driving).
2. Excessive sleepiness should be distinguished from fatigue and abulia, which have a much wider range of causes. A sleepy patient actually falls asleep rather than feels unwilling or too weak to engage in activities.
Pathophysiology
1. The causes of daytime sleepiness can be categorized as follows:
a. Insufficient or fragmented amount of sleep the night before
b. Disorders in sleep drive
2. The intrinsic drive to sleep is dependent on two main factors: (a) homeostatic, determined by prior wakefulness, and (b) circadian, determined by the individual’s current phase of the circadian rhythm. Under normal conditions, these two factors function synchronously to ensure continuous alertness during the “biological day” and continuous sleep during the “biological night.” The precise timing of sleep in relation to these idealized periods is modulated by ambient light, environmental conditions that promote or impede sleep, medications, and elective or forced wakefulness.
3. Insufficient sleep is the most common cause of excess daytime sleepiness among both adults and children. It can be because of self-inflicted sleep restriction to increase productivity or other environmental factors or because the time allotted for sleep is not the time when the drive to sleep is high (circadian misalignment because of jet lag, shift work, or other circadian rhythm disorders). It can lead to both sleepiness, and to other serious consequences, including poor concentration, lack of productivity, as well as putative impairments in immune and metabolic functions.
4. Sleep fragmentation can be caused by environmental factors, medical or neurologic disease, and primary sleep disorders. Physiologically, most adults need between 7 and 9 hours of sleep. If sleepiness is present even after an adequate amount of sleep, and in the absence of any sleep fragmenting disorders (sleep apnea, movement disorders, etc.), there may be an abnormally high sleep drive. This can be caused by: (a) medications, (b) medical or neurologic disorders,
(c) circadian misalignment (eg, jet lag), or (d) primary disorders of sleep drive (such as narcolepsy and idiopathic hypersomnia).
Diagnosis
1. Sleep quantity is determined by history, sleep logs, and actigraphy. Polysomnography (PSG) is indicated if a primary sleep disorder is suspected.
2. The Epworth sleepiness scale (Table 8-1) can help quantify the complaint.
3. Objectively, sleepiness can be measured by the multiple sleep latency test (MSLT), in which the patient is allowed five nap opportunities, each 2 hours apart, beginning 2 hours after awakening. An average latency to sleep onset of less than 8 minutes across the five naps is considered indicative of pathologic daytime sleepiness. The appearance of more than one rapid eye movement (REM) period during the MSLT naps or during the overnight PSG indicates REM dysregulation, a result of either sleep loss or narcolepsy, whereas an average sleep latency of less than 8 minutes without REM periods indicates other causes of sleepiness, such as idiopathic hypersomnia.
4. In individuals with suspected narcolepsy with cataplexy, orexin can be measured in cerebrospinal fluid. An orexin A (hypocretin-1) level of ≤110 pg/mL is considered confirmatory.
Table 8-1 Epworth Sleepiness Scale | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Treatment and Prognosis
1. Treatment depends on establishing the underlying cause.
2. When sleepiness persists after the underlying cause had been adequately addressed, wake-promoting medications (Table 8-2) can be used.
3. The clinician should discuss the hazards of drowsy driving and other situations for which alertness is crucial for safety. Even healthy individuals often underestimate their degree of sleepiness.
Table 8-2 Stimulant Medications | ||||||||||||||||
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EXCESS DAYTIME SLEEPINESS AS A RESULT OF MEDICAL AND NEUROLOGIC DISEASE
Background and Pathophysiology
Numerous neurologic, medical, and psychiatric states and diseases cause sleepiness, either by disrupting the mechanisms involved in sleep homeostasis or by disrupting nighttime sleep. The major causes are as follows:
1. Neurologic causes of sleep fragmentation
a. Abnormal movements: Tremor and inability to shift positions in bed in Parkinson disease and in other neurodegenerative conditions.
b. Seizures: Either as a cause or as a consequence of fragmented sleep.
c. Spasticity: As a result of stroke, spinal cord lesion, multiple sclerosis (MS), or other conditions.
d. Nocturia: In MS, diabetes, and other conditions.
e. Comorbid primary sleep disorder: Examples include REM behavior disorder, seen in more than one-third of patients with synucleinopathies. Periodic limb movement disorder (PLMD) is commonly seen among patients with peripheral neuropathy, spinal cord lesions, and Parkinson disease. Obstructive sleep apnea (OSA) is particularly common in patients who have had strokes, in patients with amyotrophic lateral sclerosis, and in patients who have cervical spinal cord lesions. Patients with post-polio syndrome have an increased risk for both OSA as well as central sleep apnea (CSA).
2. Medical conditions that prevent or disrupt sleep
a. Medications: A detailed description can be found in Table 8-3.
b. Pain: Virtually all forms of acute and chronic pain are responsible for poor sleep and subsequent sleepiness. The pain produced by cancer, spondylosis, rheumatologic conditions, fracture, and the postoperative state is common and may not be revealed without careful acquisition of the patient’s history. Certain nocturnal pains are, of course, characteristic of serious conditions such as spinal and brain tumor. Skin diseases with itching and gastroesophageal reflux are derivatives of this category.
c. Nocturia: Independent of neurologic disease, the common problem of prostatism causes frequent nocturnal arising from bed.
d. Cardiopulmonary failure: Disrupts sleep as a result of dyspnea, especially if there is orthopnea.
e. Psychiatric disorders
1) Anxiety states: Both acute situational and chronic anxiety associated with depression are highly likely to change sleep, mostly with insomnia.
2) Mania: Usually associated with reduced need for sleep but not typically causing secondary daytime sleepiness.
Table 8-3 Medications Associated With Excessive Daytime Sleepiness | ||||||||||||||||||||||||
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Prognosis
Prognosis depends on the underlying cause. It is best for remediable pain, anxiety states, and circadian and environmental disruption that are amenable to simple rectification.
Diagnosis
Diagnosis is made by history of one of the described disturbances and by confirming the presence of sleepiness by observation or multiple sleep latency testing.
Treatment
The first step of treatment is control of sleep disrupting factors. In patients in whom sleepiness persists thereafter, wake-promoting medications (modafinil, armodafinil, stimulants) can be helpful to control residual sleepiness with minimal side effects. Counseling about driving may be appropriate as well because episodes of irresistible sleepiness may occur, not preceded by obvious warning.
PRIMARY SLEEP DISORDERS LEADING TO EXCESSIVE SLEEPINESS
Sleep Disordered Breathing
Background
1. Major subtypes include:
a. OSA: Characterized by repetitive episodes of pharyngeal collapse during sleep.
b. CSA: Characterized by periods of absent respiratory effort. These may occur sporadically or in a cyclic pattern (eg, Cheyne-Stokes respiration).
c. Sleep-related hypoventilation syndromes: Periods of decreased ventilation with profound hypercapnia, most commonly associated with neuromuscular weakness or chest wall abnormalities.
2. Sleep disordered breathing causes daytime sleepiness secondary to fragmentation of sleep and intermittent hypoxia.
History
The patient may present with excessive sleepiness, sleep fragmentation, or in some cases a complaint of insomnia. A bed partner may report snoring, pauses in breathing, or apparent arousals, manifesting with motor restlessness. Many patients complain of difficulty with concentration and memory, or mood disturbance. Less common complaints include morning headache and sexual difficulties.
Pathophysiology
1. In OSA, there is respiratory obstruction, leading to partial or complete cessation of breathing despite present effort to breathe. The pharyngeal dilator muscle is less active during sleep, and the uvula or tongue or both fall and either partially or completely occlude the airway. Risk factors include obesity, advanced age, male gender, and anatomical features, such as a small airway, retrognathia, and macroglossia.
2. CSA presents with episodes of absent effort to breathe. There are two basic mechanisms that trigger central respiratory events: (a) post-hyperventilation central apnea, which may be triggered by a variety of clinical conditions, and (b) central apnea secondary to hypoventilation, which can be because of medications that affect the respiratory drive (particularly opioids) or pathology that affects the medulla (such as a Chiari malformation), or idiopathic conditions.
3. CSA of the Cheyne-Stokes type is most commonly seen in patients with systolic congestive heart failure (CHF) but may occur with neurodegenerative disorders.
4. Sleep-related hypoventilation in patients with neuromuscular weakness is exacerbated by sleep-related changes in muscle activation especially during REM sleep when ventilation is primarily maintained by diaphragm activation.
Prognosis
1. The prevalence and severity of OSA increases with age. Increasing data suggest that OSA is also independently associated with cardiovascular diseases such as myocardial infarction and stroke.
2. Prognosis for idiopathic CSA is less well defined.
3. Cheyne-Stokes respirations in patients with CHF are an independent predictor of mortality.
4. Sleep-related hypoventilation in patients with neuromuscular disease is a precursor to daytime respiratory failure.
Diagnosis
The gold standard for diagnosis is overnight attended PSG. However, in many cases, a home sleep apnea test can be used as a more cost-effective measure. It is important to note that a home sleep apnea test (a) does not typically include any central nervous system (CNS) measures (ie, it cannot determine reliably the amount of sleep during the test), (b) may in some cases underestimate severity and thus a normal home test does not rule out presence of sleep apnea, and (c) there is no measure of motor activity. The severity of disease is quantified by the apnea-hypopnea index (number of abnormal respiratory events per hour of sleep) or AHI. By current criteria, an AHI index of more than 5 per hour is considered abnormal and warrants treatment in the presence of clinical symptoms, whereas an AHI of greater than 15 per hour warrants treatment even in the absence of clinical symptoms because OSA may increase the risk of major comorbidities, such as hypertension, type 2 diabetes, myocardial infarction, and stroke.
Treatment
1. OSA
Conservative measures that may improve OSA include weight loss and avoidance of alcohol and sedative medications.
a. In some patients, respiratory events occur primarily while sleeping supine. For them, the use of wedge pillows or similar shaped objects in the nightshirt or gown can be used to limit sleep in this position.
b. Positive airway pressure (PAP) therapy applied via a nasal mask is the primary modality of therapy. It works as a pneumatic splint, preventing airway collapse. It can be delivered continuously (continuous positive airway pressure [CPAP]) or as bilevel (bilevel positive airway pressure [BiPAP], which provides a lower pressure on expiration from inspiration). It may lead to decreased daytime sleepiness and improved overall function and quality of life, and in some studies, it shows lower blood pressure in comparison to placebo.
c. PAP therapy can be started via autotitrating PAP machines. Follow-up is needed to establish adherence, ie, that the patient consistently uses PAP during sleep, as well as efficacy, ie, normalization of AHI (AHI target <5/h).
d. Oral appliances are custom-made mouthpieces that function by advancing the mandible, thus enlarging the pharyngeal airway. They are effective for patients with mild-to-moderate OSA, and efficacy ranges from 60% to 80%. Many patients prefer these devices to PAP because of ease of use.
Surgical therapies of OSA include:
a. Hypoglossal nerve stimulation therapy implant—this may be appropriate for the following situations:
1) In those who do not have major comorbidities (such as severe cardiopulmonary disease or neuromuscular disease), and have no major severe anatomic abnormalities or the upper airway
2) BMI < 33, AHI 15 to 65, and intolerant to PAP therapy
b. Minimally invasive procedures (such as radiofrequency uvular ablation)
c. More invasive procedures such as uvulopalatopharyngoplasty (UPPP).
d. Success rates for surgery vary depending on the procedure, but for UPPP, the success rates are approximately 40% to 50%.
In a minority of patients whose apnea is adequately treated, excessive daytime sleepiness remains a significant problem. In these patients, the addition of wake-promoting medications has been shown to improve sleepiness.
2. CSA
a. Treatment of CSA is substantially more difficult than OSA. Careful review of contributing medications and limiting use of opiates and alcohol are imperative.
b. In some situations, medications such as acetazolamide may be helpful.
3. Cheyne-Stokes respiration
a. If associated with CHF, optimizing therapy for heart failure is the primary therapy (after load reduction, diuretics, β-blockers, etc.). A follow-up study is recommended to confirm that measures have been effective.
b. Other available treatments include supplemental oxygen and nasal PAP.
4. Adaptive servoventilation (ASV)
a. ASV is a new method of treatment that uses an automatic, minute ventilation-targeted device that performs breath-to-breath analysis and adjusts its settings accordingly. It is a promising treatment option for patients with CSA. It can also be helpful in treating patients with OSA, who also have central apneas or Cheyne-Stokes respiration. However, ASV should be considered with caution in patients with a decreased ejection fraction because a recent analysis demonstrated an increased risk of cardiac mortality in patients with a left ventricular ejection fraction (LVEF) of ≤45%. As a result, current guidelines do not recommend the use of ASV in these patients.
NARCOLEPSY
Background
Narcolepsy is present in 0.05% of adults (prevalence similar to that of MS). Onset is usually in the second decade of life, but initial appearance of symptoms in the 30s is common. The mean time between symptom onset and diagnosis is frequently prolonged because of misdiagnosis.
History
Narcolepsy is characterized by excess daytime sleepiness and dysregulation of REM processes. The classic tetrad includes:
1. Sleepiness: Patients describe episodes of irresistible need to fall asleep (sleep attacks) or a general tendency to fall asleep in any passive situation. Ironically, nocturnal sleep is often fragmented. Naps are typically short and refreshing.
2. Sleep paralysis: The appearance of REM atonia in early stages of sleep or wakefulness, leading to brief (seconds to minutes), usually frightening, inability to move voluntary musculature in the presence of full alertness, either on awakening or at the transition from wake to sleep. Concomitant paralysis of the accessory muscles of inspiration may result in the sensations of dyspnea.
3. Cataplexy: Episodes of transient loss of muscle tone, stimulated by emotions, most commonly laughter or telling a joke. The episodes are brief (<2 minutes) and usually bilateral. There may be transient loss of deep tendon reflexes. Based on the presence or absence of cataplexy, narcolepsy is classified as narcolepsy type 1 (with cataplexy) or type 2 (without cataplexy).
4. Hypnagogic (at sleep onset) or hypnopompic (at sleep offset) hallucinations: It is the appearance of the hallucinatory phenomena of dreams during wakefulness. Usually these are fragmentary and brief (hearing the telephone or one’s voice being called) or seeing a shadow of a person, although rarely they may be more elaborate.
a. Sleep paralysis and hypnagogic hallucinations are occasionally reported in isolation by individuals without narcolepsy.
b. Narcolepsy is currently classified as existing with or without cataplexy. The exact percentage of individuals with the excess daytime sleepiness of narcolepsy with cataplexy is unclear, but it is thought to be 50% to 80% of cases.
Pathophysiology
Progress in understanding the pathophysiology of narcolepsy has been made in the past 10 years, stimulated by findings that HLA genotype DQB1*0602 is much more common in individuals with the disease (85% of narcoleptics vs 25% of the general population). Knockout mice for the hypothalamic peptide hypocretin (orexin) exhibit behavioral states consistent with narcolepsy. In human narcolepsy, a reduction in the number of hypothalamic neurons responsible for the production of hypocretin (orexin) and the absence of this ligand in the cerebrospinal fluid (CSF) confirm the importance of hypocretin in narcolepsy with cataplexy.
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